Thermal Gel in the Treatment of Low-Grade Upper Tract Urothelial Carcinoma

Upper tract urothelial carcinoma (UTUC) is a rare malignancy, making up only 5-10% of all urothelial carcinomas.¹ The standard approach for management of high-grade UTUC is radical nephroureterectomy, whereas kidney-sparing treatment is recommended for patients with low-grade disease and small, favorably located tumors with compromised renal function or a  solitary kidney.^2,3 Kidney-sparing treatments include ureteroscopic or percutaneous laser ablation with or without antegrade or retrograde administration of adjuvant intraluminal therapies such as bacillus Calmette-Guérin (BCG), mitomycin, or gemcitabine. However, until recently, barriers to use of these topical therapies have been the limitations on drug concentration and dwell time, as well as poor drug interface with upper tract mucosa, due to the continuous downflow of urine produced by the kidneys.^4,5 Thermoregulation gels were developed to counteract these barriers to installation therapy.

UGN-101 (mitomycin for pyelocaliceal solution) is a formulation of mitomycin designed to provide extended dwell and contact time of mitomycin with the surface of the upper urinary tract. It consists of mitomycin and a RTGel reverse thermal hydrogel (4 mg mitomycin per mL gel), which is liquid when chilled and converts to a semisolid gel at body temperature following instillation into the upper tract.^6,7  Normal urine flow dissolves the gel, allowing tissue exposure to mitomycin over a period of 4-6 h. UGN-101 (Jelmyto^®, UroGen Pharma) was approved by the US Food and Drug Administration (FDA) in April 2020 for use in adults with low-grade UTUC.⁸ based on efficacy data from the pivotal phase 3 Optimized DeLivery of Mitomycin for Primary UTUC Study (OLYMPUS; NCT02793128). Interim data from the OLYMPUS trial were reported in The Lancet around the same time⁹ and the results of the final analysis were presented at the 2021 annual meeting of the American Urological Association (AUA)¹⁰ and subsequently published in the Journal of Urology in December 2021.¹¹

The OLYMPUS Trial

OLYMPUS was a prospective, open label, single-arm trial, carried out at 24 academic centers in the US and Israel, that evaluated treatment with UGN-101 for primary or recurrent, biopsy-proven, low-grade UTUC.^9,11 Eligible patients were aged ≥18 years, with one or more lesions measuring 5-15 mm and Eastern Cooperative Oncology Group (ECOG) performance status score <30 (Karnovsky performance status >40). Patients with lesions larger than 15 mm were eligible for endoscopic downsizing before the start of the study. Patients with multifocal and/or bilateral disease were included in the study if one renal unit was disease-free before enrollment. Lesions in the ureter required ablation to be included. All patients had adequate organ and bone marrow function as determined by white blood cell count, platelet count, hemoglobin, bilirubin, and liver and kidney function.

Study treatment consisted of six once-weekly treatments with UGN-101(4 mg mitomycin per mL gel) delivered via retrograde ureteral catheterization. The volume of UGN-101 volume was fluoroscopically guided up to a maximum of 15 mL (maximum dose 60 mg). Procedures were done in various clinical settings, including hospital operating rooms, outpatient surgical centers, and physicians’ offices, under general or local anesthesia according to patient and provider preference.

Patients were evaluated by ureteroscopy, selective cytology, and for-cause biopsy at 4 -6-weeks after initial therapy via ureteroscopy, selective cytology, and if necessary, biopsy. Patients with a complete response continued to undergo quarterly surveillance and were eligible for up to 11 once-monthly maintenance treatments with UGN-101. Patients with no complete response or a partial response were referred for standard-of-care therapy as directed by the treating urologist. Durability of response was evaluated at 3, 6, 9, and 12 months.

Between April 2017 and November 2018, 71 patients received ≥1 dose of UGN-101, of whom 61 (86%) completed 6 treatments with UGN-101,⁹ 25% under general anesthesia and the remainder local anesthesia or sedation respectively. During the initial 6-week treatment period, 13% of patients discontinued treatment due to adverse events, the most frequent reason for stopping therapy.

Patient Analyses

The first analysis, based on data up to May 22, 2019, showed that at the primary evaluation visit, 42 of 71 (59%) patients had achieved a complete response, defined as negative 3-month ureteroscopic evaluation, negative cytology, and negative for-cause biopsy.⁹ Median follow-up in these patients was 11 months. Subgroup analyses revealed no effect of age, gender, lesion debulking, number of treatments, or past urothelial carcinoma episodes on complete response.

Of the 42/71 patients who had achieved a complete response at primary disease evaluation, 41(58%) were eligible for evaluation of response durability.¹¹ Most of these patients were white, male, aged >70 years, and had two kidneys. Around 29% received no maintenance therapy, which 71% received ≥1 dose of maintenance therapy. Among the 41 patients followed over a median of 11.8 months, 23 (56%) remained in complete response after 12 months. Kaplan-Meier analysis estimated durability of response at 82%, 12 months after primary disease evaluation.  Subgroup analyses did not reveal any individual parameter that affected durability of response. There also appeared to be no association between durability of response and maintenance treatment. Eight patients had disease recurrence, the earliest of which were 3 recorded, 3 months after primary disease evaluation. Among the 8 patients considered to have a partial response at the primary evaluation visit, there was clinical benefit resulting from modification of their treatment plans.

Treatment-emergent adverse events (TAEs) did not differ greatly quantitively or qualitatively between the interim and final analyses of the trial. The final analysis showed that the most common TEAEs were ureteric stenosis, urinary tract infection, hematuria, and flank pain, and most were related to study drug or procedure.  Differences were seen in the incidences of TEAEs between patients who received ≤6 instillations of UGN-101(induction only) and those who received ≥7 instillations (≥1 maintenance instillation). An association was detected total number of UGN-101 instillations and the most commonly reported renal and urinary TEAEs; for example, ureteric stenosis was reported in 69% of patients who received ≥7 instillations of UGN-101 vs 29% who received ≤6 instillations. In addition to 3 deaths reported in the interim analysis, 2 patients died with further follow-up, but none of the deaths was considered related to treatment.

Study Summary

Limitations of OLYMPUS included the small study population, reflecting the rarity of UTU, which could limit the generalizability of the findings about the durability of complete response. In addition, the absence of a control group may introduce bias, especially under—or overrepresentation of harms. Furthermore, it is well documented that low-grade disease on biopsy does not necessarily correlate to final pathology, and it is possible that high-grade tumor burden was present, but not seen in biopsy.¹² This should be considered when selecting patients who might benefit from conservative management.

In summary, the mitomycin-containing reverse thermal gel, UGN-101, addresses an important barrier to the instillation of chemotherapy, allowing installation of a chemotherapeutic agent that can maintain its integrity long enough to exert a therapeutic effect. The OLYMPUS trial indicated that the benefit-risk profile of UGN-101 for induction treatment of low-grade UTUC was favorable, and that kidney-sparing endoscopic treatment can be augmented in patients with multifocal disease and those with tumors that are difficult to treat endoscopically. This can potentially be a viable conservative option for the management of low grade UTUC. However, further study is needed to determine the ideal regimen and the role of maintenance therapy, as well as the feasibility of performing installation and surveillance under local anesthesia to potentially reduce the total cost of therapy.

In addition, the OLYMPUS trial utilized a retrograde delivery system, which could have potentially increased the rate of adverse events such as ureteral stricture. A recent study that evaluates a small group of patients who received UGN-101 via an antegrade approach suggested that this approach has the potential to increase patient comfort, improve logistics, and decrease risk of adverse events.¹³

David Ambinder, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include surgical education, GU oncology and advancements in technology in urology. A significant portion of his research has been focused on litigation in urology. 

References

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